Jung Eun Nam

Selective hepatic insulin resistance is characterized by preserved lipogenesis despite the failure to suppress gluconeogenesis, yet the detailed molecular mechanisms underlying this paradox remain incompletely understood. Here, we identify serotonin as an insulin independent regulator that differentially regulates hepatic lipid and glucose metabolism in insulin resistant states. Serotonin promoted hepatic lipogenesis through HTR2Amediated activation of the Ca ²⁺ -PI3K-AKT-mTORC1 signaling cascade, leading to SREBP1 activation independently of insulin receptor. In parallel, serotonin signaling through HTR2Bstimulates hepatic gluconeogenesis via a Ca ²⁺ -NO-cGMP-PKG pathway, resulting in CREB phosphorylation independently of PKA. Genetic disruption of HTR2A selectively attenuated hepatic lipogenesis, whereas deletion of HTR2B suppressed gluconeogenic gene expression and hepatic glucose production without affecting lipogenesis. Together, these findings establish serotonergic regulation as a dual, insulin independent driver of hepatic lipogenesis and gluconeogenesis under insulin resistant conditions, providing a mechanistic explanation for selective hepatic insulin resistance and identifying serotonin receptors as potential therapeutic targets for metabolic disease.

Background: Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine neurotransmitter that has various functions in central and peripheral tissues. While 5-HT is known to regulate various biological processes in liver, direct role of 5-HT and its receptors, especially 5-HT receptor 2A (HTR2A) and HTR2B, in development and progression of alcoholic liver disease (ALD) in vivo is not well understood.Methods: Blood 5-HT level was measured from both human ALD patients and ethanol (EtOH) diet-fed mouse models. Gut-specific tryptophan hydroxylase 1 (Tph1) knockout mice, liver-specific Htr2a knockout mice, and liver-specific Htr2b knockout mice were fed with EtOH diet. Then we evaluated liver damage, hepatic steatosis, endoplasmic reticulum (ER) stress, and inflammation.Results: Blood 5-HT concentrations are increased in both humans and mice with ALD. Both gut-specific Tph1 knockout and liver- specific Htr2a knockout mice are resistant to steatosis by down-regulating lipogenic pathways in liver of chronic EtOH diet-fed mice. Moreover, genetic inhibition of both gut-derived serotonin (GDS) synthesis and hepatic HTR2A signaling prevents ER stress in liver of chronic EtOH diet-fed mice. Additionally, we found that ablation of HTR2A signaling protects against disease progression by attenuating liver injury and inflammation in chronic plus binge EtOH diet-fed mice. Also, inhibiting HTR2A signaling ameliorates alcohol-induced liver injury and ER stress in an acute EtOH diet-fed mice model.Conclusion: GDS directly regulates lipogenesis and ER stress via signaling through hepatic HTR2A in the context of ALD. Inhibiting HTR2A signaling protects against alcohol-induced steatosis, liver injury and disease progression in various ALD mouse models and may also provide a novel therapeutic strategy for ALD.